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Structural basis for the transcriptional regulation of membrane lipid homeostasis

Nature Structural & Molecular Biology volume 17, pages 971975 (2010) | Download Citation

Abstract

DesT is a transcriptional repressor that regulates the genes that control the unsaturated:saturated fatty acid ratio available for membrane lipid synthesis. DesT bound to unsaturated acyl-CoA has a high affinity for its cognate palindromic DNA-binding site, whereas DesT bound to saturated acyl-CoA does not bind this site. Structural analyses of the DesT–oleoyl-CoA–DNA and DesT–palmitoyl-CoA complexes reveal that acyl chain shape directly influences the packing of hydrophobic core residues within the DesT ligand-binding domain. These changes are propagated to the paired DNA-binding domains via conformational changes to modulate DNA binding. These structural interpretations are supported by the in vitro and in vivo characterization of site-directed mutants. The regulation of DesT by the unsaturated:saturated ratio of acyl chains rather than the concentration of a single ligand is a paradigm for understanding transcriptional regulation of membrane lipid homeostasis.

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Acknowledgements

We thank M. Frank for his technical assistance and the St. Jude Protein Production Facility for the expression and purification of DesT and its SeMet-labeled derivative. This work was supported by US National Institutes of Health grant GM34496 (C.O.R.), Cancer Center Support Grant CA21765 and the American Lebanese Syrian Associated Charities. Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID and 22-BM beamlines at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38.

Author information

Author notes

    • Yong-Mei Zhang

    Present address: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.

Affiliations

  1. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Darcie J Miller
    •  & Stephen W White
  2. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Yong-Mei Zhang
    • , Chitra Subramanian
    •  & Charles O Rock

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Contributions

D.J.M. and S.W.W. designed and executed the crystallography experiments; Y.-M.Z., C.S. and C.O.R. designed and executed the biochemical and genetic experiments; all authors participated in writing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stephen W White.

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DOI

https://doi.org/10.1038/nsmb.1847

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